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NADP + is an endogenous PARP inhibitor in DNA damage response and tumor suppression.
- Source :
-
Nature communications [Nat Commun] 2019 Feb 11; Vol. 10 (1), pp. 693. Date of Electronic Publication: 2019 Feb 11. - Publication Year :
- 2019
-
Abstract
- ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD <superscript>+</superscript> as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP <superscript>+</superscript> , an NAD <superscript>+</superscript> derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP <superscript>+</superscript> acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP <superscript>+</superscript> impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP <superscript>+</superscript> as an endogenous PARP inhibitor that may have implications in cancer treatment.
- Subjects :
- ADP-Ribosylation
Animals
Biomarkers
Cell Line, Tumor drug effects
DNA Repair
Fanconi Anemia Complementation Group Proteins genetics
Female
Humans
Mice
NAD pharmacology
Ovarian Neoplasms
Phosphotransferases (Alcohol Group Acceptor) drug effects
Poly ADP Ribosylation drug effects
RNA Helicases genetics
Antineoplastic Agents pharmacology
DNA Damage drug effects
NADP antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Poly(ADP-ribose) Polymerases drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30741937
- Full Text :
- https://doi.org/10.1038/s41467-019-08530-5